GENETIC ANALYSIS OF VERTEBRAL STRENGTH

椎骨强度的遗传分析

• 批准号: 6349975
• 负责人: CHARLES H TURNER
• 金额: $ 42.87万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-08 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6349975
• 关键词: alleles; bone density; bone development; computed axial tomography; femur; gene expression; gene interaction; genetic mapping; genetic markers; genetic polymorphism; genotype; growth /development; laboratory mouse; physical property; polymerase chain reaction; quantitative trait loci; vertebrae

While many environmental factors (i.e., diet and exercise) affect bone accumulation during growth, studies in twins have determined that about 70 percent of the variability in bone mineral density is genetically based, yet there is still much work to be done before the genes linked to bone fragility are identified. One useful strategy for uncovering the complex gene interactions contributing to bone fragility employs inbred strains of mice differing in bone mineral density and strength. Individuals within an inbred strain are identical "twins" and their environments can be closely controlled. Two inbred strains of mice with substantially different femoral bone densities are C3H/HeJ or C3H (high bone density) and C57BL/6J or B6 (low bone density). Planned matings between these inbred strains allow the segregation of genetic alleles; alleles important for BMD or bone strength in the progenitors will affect those traits in the offspring. Our preliminary data demonstrate that both B6 and C3H strains contain alleles that promote both high and low vertebral strength. Our results also suggest that midshaft femoral and vertebral strengths are regulated by different genes. As a result, we propose that there is differential genetic regulation of cortical and trabecular bone microstructures during growth and developement. We will test the following hypotheses: 1) vertebral fragility is regulated by different genes compared to bone mineral density of the femur, a phenotype that was previously characterized; 2) B6 and C3H alleles that affect vertebral fragility can be isolated in congenic strains of mice; 3) B6 and C3H alleles affect both cortical and trabecular microstructural organization of the vertebrae and thus vertebral fragility; 4) the genetic differences in vertebral biomechanical properties and microstructural organization become apparent in mice during the rapid growth phase (2-26 wks of age). We will use quantitative trait loci (QTL) analysis of an F2 population from C3H and B6 progenitor strains to determine correlations between genotype (B6 and C3H alleles) and a phenotype determined from biomechanical testing of the lumbar vertebrae. Congenic strains and recombinant inbred strains from the B6C3H-F2 population will be characterized using biomechanical testing and micro-computed tomography (muCT) to evaluate femoral and vertebral microstructure. Finally, the genetic effects on femoral and vertebral microstructure during growth and development will be analyzed for different inbred strains of mice using muCT and biomechanical testing.

尽管许多环境因素（即饮食和运动）会影响生长过程中的骨骼积累，但对双胞胎的研究确定，骨矿物质密度的变异性的约70％是基于遗传的，但是在确定与骨骼脆弱性相关的基因之前，仍有很多工作要做。 揭示有助于骨骼脆弱的复杂基因相互作用的一种有用策略采用骨矿物质密度和强度不同的小鼠的近交菌株。 近交菌株中的个体是相同的“双胞胎”，并且可以密切控制其环境。 股骨密度大大不同的两种近交菌株是C3H/HEJ或C3H（高骨密度）和C57BL/6J或B6（低骨密度）。 这些近交菌株之间的计划均可隔离遗传等位基因。对祖细胞中BMD或骨骼强度重要的等位基因将影响后代中的那些特征。 我们的初步数据表明，B6和C3H菌株都包含促进高和低椎骨强度的等位基因。 我们的结果还表明，股骨和椎骨强度由不同的基因调节。 结果，我们建议在生长和发展过程中对皮质和小梁骨微结构的遗传调节差异。 我们将检验以下假设：1）与股骨的骨矿物质密度相比，椎骨脆弱性受到不同基因的调节，股骨的骨矿物质密度是先前表征的表型； 2）影响椎体脆弱性的B6和C3H等位基因可以在小鼠的先天性菌株中分离出来； 3）B6和C3H等位基因影响椎骨的皮质和小梁微结构组织，从而影响椎骨脆弱性。 4）在快速生长阶段（年龄为2-26周），椎体生物力学特性和微结构组织的遗传差异变得显而易见。 我们将使用来自C3H和B6祖细胞菌株的F2种群的定量性状基因座（QTL）分析来确定基因型（B6和C3H等位基因）之间的相关性以及由腰椎椎骨的生物力学测试确定的表型。 B6C3H-F2种群中的先天性菌株和重组亲，使用生物力学测试和微型计算层析成像（MUCT）来评估股骨和椎骨微结构。 最后，将对使用MUCT和生物力学测试的不同近交菌株分析对生长和发育过程中股骨和发育过程中对股骨和发育过程中对股骨微结构的遗传作用。